1. Field of the Invention
This invention relates to compositions and methods for treating diabetes.
2. Discussion of the Background
Diabetes mellitus has been defined as "a clinical syndrome characterized by a relative or inadequate deficiency of insulin or by a resistance to the action of insulin." (Ratner R E: Management of Diabetes Mellitus: Perspectives of Care Across the Lifespan. 1992, Mosby.) The definition is appropriate to the forms of diabetes that can be identified as insulin dependent diabetes mellitus (IDDM), or Type I, that requires injections of insulin to manage their loss of or insufficient pancreatic .beta.-cell production of insulin.
Non-insulin dependent diabetes mellitus patients (NIDDM), or Type II, frequently have an increase or partial deficiency of insulin production, depending on how long the NIDDM has persisted. Regardless of the patients blood level of insulin, the hypoglycemic response to insulin is usually impaired. Patients thus exhibit postprandial and often fasting hyperglycemia, sometimes despite markedly elevated levels of insulin. Of the 13 to 15 million diabetic patients in the USA, it is estimated that up to 90% are NIDDM. By the use of surveys designed to represent their distribution, half of these NIDDM patients are undiagnosed, hence untreated. (Harris M I: Undiagnosed NIDDM: Clinical and Public Health Issues. Diabetes Care 1993;16:642-652.) Insulin production may or may not be adequate for glycemic control by proper diet and/or drug therapy.
Two determinants that influence importantly insulin resistance of cell membrane to glucose entry are: (1) availability of insulin receptors at the cell membrane, the number and activation of which is insulin-dependent, and (2) the plasma level of free fatty acids (FFA) from foodstuff and/or the lipolysis of triglyceride stores, principally in adipose tissue. Lipolysis induced by hormones, such as Norepinephrine, increases FFA blood levels available especially to muscle as a sustaining source of energy. As the blood level of FFA increases, resistance of the cell membrane to glucose uptake (insulin resistance) increases. Conversely, increased insulin blood levels as induced by the endogenous generation of hyperglycemia or by a high glucose meal (a glucose tolerance test for example) can inhibit lipolysis, and thus reduce serum FFA levels and its impedance of glucose uptake by the cells. In the non-diabetic, active person this shifting balance of a normal range of glycemia, insulin blood level and FFA lipemia makes possible exertion, sustained physical effort and consciousness over a period of hours or days between meals.
The NIDDM person is less capable of sustaining this dietary shifting balance of glycemia, insulin and FFA levels. Some may be able to approximate a normal metabolic balance if a proper diet of carbohydrate, fat and protein intake is adhered to. Exercise, a balanced life style and adjustment to or relief from stress contribute together with diet as basic therapy for these patients. Weight reduction may be an important feature of this behavior pattern since overweight and hypertension are common characteristics of NIDDM diabetes.
If this regimen of diet, exercise and adjustment to stress is insufficient to control blood sugar within appropriate limits, a sulfonylurea drug may suffice to lower blood glucose levels toward normal. These drugs are reported to stimulate insulin release from pancreatic .beta.-cells and to increase insulin sensitivity at cell surfaces. They are usually taken just before a meal or meals. The initial (primary) response to sulfonylureas may be inadequate in 25 to 30% of patients. With time another 5 to 10% of patients develop resistance to these drugs. (Ilarde A, Tuck M: Treatment of non-insulin-dependent diabetes mellitus and its combinations. Drugs-Aging 1994;4:470-491.)
Sulfonylureas are not antihypertensive agents nor do they lower hyperlipidemic blood levels. Thus, ancillary antihypertensive and antihyperlipidemic therapy is required to diminish the high risk of cardiovascular insults such as atherosclerosis and coronary heart disease--the most frequent cause of death of these patients.
Such generally employed antihypertensive agents as thiazides and .beta.-adrenergic blocking drugs adversely affect glucose and lipid metabolism in NIDDM persons. Most, but not all, calcium channel blocking drugs are less offensive in this regard. Angiotensin converting enzyme inhibitors do not reduce either hyperglycemia or hyperlipidemia. Their antihypertensive effect is their supportive role for these diabetic patients. Hydroxymethylglutaryl-coenzyme-A reduction inhibitors of cholesterol synthesis are relatively ineffective in lowering the frequent hyperlipidemia derived from triglyceride synthesis or lipolysis.
Nicotinic acid inhibits triglyceride hydrolysis to FFA and glycerol but is reported to be contraindicated for diabetics. (Molnar G D, Berge K G, Rosevear J W, McGuckin W F, Achor RWP: The effect of nicotinic acid in diabetes mellitus. Metabolism 1964;13;181-190.) Amiloride, a 2,4,5-tri-polar substituted pyrazinoic acid derivative, is commonly employed in formulation with a thiazide (hydrochlorothiazide) so that its potassium-retaining characteristic will offset the kaliuresis induced by the thiazide. However, amiloride or its thiazide combination should be avoided for diabetic patients because of the possibility of inducing hyperkalemia as well as hyperglycemia and hyperuricemia.
There is accordingly a need for a compound that can safely address these several needs of NIDDM patients for reduction and control of hyperglycemia, of insulin, of free fatty acid and triglyceride blood levels, and of essential (adrenergic) hypertension.
While studying pyrazinoylguanidines and their 3-amino analogs as inhibitors of urea and salt reabsorption by the kidney (i.e., as hyperuretic and saluretic agents) (Beyer K H, Gelarden R T, Vesell E S: Inhibition of urea transport across renal tubules by pyrazinoylguanidine and analogs. Pharmacology 1992;44:124-138), it was discovered that in addition to lowering urea blood levels and decreasing hypertensive blood pressure (Chambers C E, Vesell E S, Heim C, Passananti G T, Beyer K H: Pyrazinoylguanidine: Antihypertensive, hypocholesterolemic and renin effects. J. Clin. Pharmacol. 1992;32:1128-1134) these compounds and in particular the representative pyrazinoylguanidine (PZG) decreased serum concentration of triglycerides and cholesterol. (Beyer K H, Ward T D, Vary J E, Gelarden R T, Knutson D W, Vesell E S: Contrasting effects of pyrazinoylguanidine and hydrochlorothiazide in patients with renal insufficiency. J. Clin. Pharmacol. 1993;33:554-561.) Furthermore, whereas PZG had no effect on normal glucose serum concentrations, it was capable of blocking the increased serum glucose and insulin concentrations normally induced by hydrochlorothiazide in the oral glucose tolerance test (GTT). (Vesell E S, Chambers C E, Passananti G T, Demers L M, Beyer K H: Effects of pyrazinoylguanidine on the glucose-fatty acid cycle in normal subjects and patients with non-insulin-dependent diabetes mellitus. J. Clin. Pharmacol. 1993;33:823-831.) These results arose from studies of effects after 3 weeks of administration of pyrazinoylguanidine (600 mg bid po drug therapy). (Vesell et al., J. Clin. Pharmacol. 34:1234-1245, 1994; U.S. Pat. No. 5,801,177).